Devices and Methods for Noninvasive Measurement of Intracranial Pressure

ABSTRACT

Provided are systems and methods for noninvasively assessing intracranial pressure by controllably osculating at least a portion of a subject&#39;s ocular globe while applying a force sufficient to collapse an intraocular blood vessel and correlating the collapse pressure to intracranial pressure. Also provided are ophthalmic components useful in ophthalmic imaging applications, such as retinal, corneal, and pupil imaging. The components may include an optical contact surface that has a radius of curvature that is greater than the radius of curvature of a subject&#39;s cornea.

RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 13/309,920, “Devices and Methods for NoninvasiveMeasure of Intracranial Pressure,” filed on Dec. 2, 2011, the entiretyof which is incorporated herein by reference for any and all purposes.

TECHNICAL FIELD

The present disclosure relates to the field of neurologicalinstrumentation and more specifically to the field of measuringintracranial pressure.

BACKGROUND

Intracranial pressure (ICP) is measured for the diagnosis and themanagement of disorders such as hydrocephalus and pseudotumor cerebri.ICP is often measured following serious head injury, stroke edema, andintracranial hemorrhage, and is also of value in the management ofcertain neurological or ophthalmic diseases that are associated withincreased cerebral pressure.

The current standard of care to measure ICP involves surgicallyinserting a sensor into the cranium through an access hole drilledthrough the skull. Present treatment techniques for monitoring ICP ormanaging intracranial hypertension (ICH) generally require invasiveplacement of subarachnoid bolts, counter-pressure epidural devices (Laddor Camino fiber-optic monitors) or intra-ventricular catheters coupledto external pressure monitors. Such surgical procedures carry the riskof complications including infections, hemorrhage, herniation, damage tonervous tissue, and death, and are very expensive. In addition,cerebrospinal fluid pressure may be altered the instant the measurementis performed as a result of leakage of cerebrospinal fluid. Despite therisks, invasive measurements of ICP are nonetheless commonplace, as theyprovide a treatment option in addition to a diagnostic option, whichnon-invasive devices cannot.

Because of these risks, ICP is only measured in patients who arecritically ill and is not a practical solution for assessing theseverity of a patient's injury or in triage. Accordingly, there is aneed for non-invasive, momentary assessment of ICP in certain acutesituations such as patients with acute shunt obstruction, in theneuro-intensive care unit (NICU) when lumbar puncture is not practical,in the emergency room or by emergency medical technicians (EMT) andother civilian and military first-responders in response to head injuryor the like.

Existing attempts to accurately and non-invasively determine ICP are notoptimal, as such approaches do not provide a reliable measure of ICP.Individual baseline variability due in part to anatomical variancesfurther limits the application of these methods. Additionally, thesemethods have demonstrated insufficient precision when compared toinvasive ICP monitors. Accordingly, there is an unmet need in the artfor easy to use, portable and inexpensive devices and methods capable ofnon-invasive determination of intracranial pressure.

Part of a routine neurologic assessment in patients with a head injuryor when elevated ICP is suspected is the pupillary reflex examination.The pupillary reflex is the response of the pupil to light and canprovide valuable information about the degree or progression of braininjury. It has been shown that patients with an abnormal pupil responsealso have significantly higher ICP than patients with normal pupillaryactivity.

Traditionally, the pupillary reflex has been subjective and determinedby waving a flashlight into a patient's eye to observe the pupil'sreactivity and thus the status of the nervous system and brain. Devicesto quantitatively assessed changes in constriction and dilatation ofpupils in response to light also exist. Such devices are expensive,serve the single function, require additional training and are notintegrated into a system for determining ICP.

Accordingly, there is an unmet need in the art for a method andintegrated instrument to measure, in a virtually simultaneous orsequential manner, a spectrum of neurological and neuro-ophthalmicindicators such as ICP, ophthalmodynamometry (ODM), IOP, pupillaryreflex and other similar functions. Such an instrument wouldsignificantly enhance the available information to assess theneurological status of the patient.

In addition to the patient conditions summarized above in which anassessment of ICP is desirable, the field would also benefit fromdevices and methods capable of providing a more accurate diagnosis ofglaucoma. Traditionally, a patient's intraocular pressure (IOP) has beento the single most important metric that determines a patient'ssusceptibility to glaucoma. Knowledge of a patient's ICP in addition toa patient's IOP will provide the clinician with the translaminarpressure (i.e., the pressure difference between IOP and ICP that isapplied to the optic nerve head), which may be a more accurate indicatorof glaucoma susceptibility than IOP alone.

SUMMARY

In a first aspect, the present disclosure provides methods of estimatingintracranial pressure in a subject, comprising imaging an intraocularblood vessel while applying a force so as to at least partiallyapplanate (i.e., flatten) or osculate (i.e., curve match), hereinafterreferred to as “osculate” or “osculating” unless specifically stated, aportion of the ocular globe so as to increase intraocular pressure to alevel sufficient to collapse an intraocular blood vessel; estimating, byone of several methods of determining intraocular pressure, theintraocular pressure that collapses the intraocular blood vessel; andcorrelating the estimated intraocular pressure that collapses theintraocular blood vessel to an estimated intracranial pressure of thesubject. Exemplary methods of determining intraocular pressure include,e.g., corneal applanation tonometry, pneumotonometry, electronicindentation tonometry, transpalpebral tonometry, contour tonometry andthe like.

In another aspect, the present disclosure provides systems for measuringintracranial pressure configured to controllably at least partiallyosculate at least a portion of the ocular globe of a subject's eye,measuring intraocular pressure and suitably collecting images fromretinal blood vessels. In one illustrative embodiment, retinal bloodvessel images are concurrently collected with a means of determiningintraocular pressure from the measured force on the ocular globe anddetermination of the area of flattening or depression of the ocularglobe.

The present disclosure further provides ophthalmic components that maybe referred herein as osculating caps. These components suitably includea body having an optical surface adapted to contact a subject's cornea,the body being adapted to engage with an applanating instrument, and thecomponent comprising a lens, a prism, or both. In some embodiments, thelens or prism is formed in the body. In others, the lens or prism isbonded to the body. The osculating cap may contain one or more indiciato assist the ICP measurement system to know its type or function.Further, the indicia may alter or control system electronics to modulatesystem operation and data collection. The ophthalmic component may, insome embodiments, include a refractive surface approximating that of aunapplanated cornea. The lens, prism, or both, may be formed on onesurface of the ophthalmic component.

The present disclosure further provides systems for imaging the retinalfundus concurrently collected with a means of determining intraocularpressure for the purposes of determining intracranial pressure in thepresence of papilledema or grading papilledema.

Further yet, the present disclosure provides systems for determiningpupillary reflex in response to light stimulation concurrently orsequentially with measuring ICP, IOP or ophthalmodynamometry (ODM).

The present disclosure also provides ophthalmic components, thecomponents suitably comprising a body having an osculating surfaceadapted to osculate a subject's ocular globe, and the body being adaptedto engage with an instrument.

Also provided are methods of estimating a pressure in a subject, themethods suitably comprising imaging an intraocular blood vessel whileapplying a force to the subject's ocular globe, the force being appliedthrough a component having a contact surface that osculates a portion ofthe subject's ocular globe, the force being sufficient to collapse anintraocular blood vessel.

Further provided are systems for measuring intracranial pressure in asubject, the systems comprising an ophthalmic component having a havingan osculating optical surface adapted to contact a subject's ocularglobe; and a force applicator.

BRIEF DESCRIPTION OF THE DRAWINGS

The summary, as well as the following detailed description, is furtherunderstood when read in conjunction with the appended drawings. For thepurpose of illustrating the invention, there are shown in the drawingsexemplary embodiments of the invention; however, the invention is notlimited to the specific methods, compositions, and devices disclosed. Inaddition, the drawings are not necessarily drawn to scale or proportion.In the drawings:

FIG. 1 depicts an exemplary intracranial pressure measuring systemaccording to the present disclosure;

FIG. 2 depicts an exemplary single image sensor optical imaging systemaccording to the present disclosure;

FIG. 3 depicts exemplary results of imaging a flat osculator accordingto the present invention;

FIG. 4 depicts an image from a single retina-cornea image sensor systemaccording to the present disclosure;

FIG. 5 depicts a first exemplary dual image sensor system according tothe present invention;

FIG. 6 depicts an exemplary retinal imaging and illumination systemshown in FIG. 5 and according to the present invention;

FIG. 7 depicts a first exemplary cross-section view of an illuminationpattern of the flat osculation interface in accordance with the presentinvention;

FIG. 8 depicts a second exemplary cross-section view of an illuminationpattern of the flat osculation interface in accordance with the presentinvention.

FIG. 9A depicts a portion of a corneal imaging and illumination systemshown in FIG. 5 and according to the present invention;

FIG. 9B depicts a corneal osculating image from the system shown in FIG.5 and according to the present invention.

FIG. 10 depicts exemplary flat osculators in accordance with the presentinvention; and

FIG. 11 depicts a second exemplary dual image sensor system according tothe present invention;

FIG. 12 depicts an exemplary flow diagram of the operation of anintracranial pressure measuring system; and

FIG. 13 depicts methods of increasing pressure in the eye with anosculating cap of the cornea; and

FIG. 14 depicts an image thru an osculating cap of the retina and theapplanation area of the cornea before and after retinal vessel collapse

FIG. 15 depicts an exemplary osculating cap mounted on the distal end ofan optical train for determining contact force using a deflecting tab.

FIG. 16 depicts methods of determining the degree of deflection of adeflection tab

FIG. 17 depicts an exemplary strain gauge pattern for measuring contactforces exerted on an osculator

FIG. 18 depicts an exemplary scheme for removably attaching anosculating cap;

FIG. 19 depicts imaging and data analysis for pupillometry; and

FIG. 20 shows representative experimental data and trend linesdemonstrating the relationship between applanation force/area to ΔIOPfor several different resting IOPs.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention may be understood more readily by reference to thefollowing detailed description taken in connection with the accompanyingfigures and examples, which form a part of this disclosure. It is to beunderstood that this invention is not limited to the specific devices,methods, applications, conditions or parameters described and/or shownherein, and that the terminology used herein is for the purpose ofdescribing particular embodiments by way of example only and is notintended to be limiting of the claimed invention. Also, as used in thespecification including the appended claims, the singular forms “a,”“an,” and “the” include the plural, and reference to a particularnumerical value includes at least that particular value, unless thecontext clearly dictates otherwise. The term “plurality,” as usedherein, means more than one. When a range of values is expressed,another embodiment includes from the one particular value and/or to theother particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “approximately” or “about,” itwill be understood that the particular value forms another embodiment.All ranges are inclusive and combinable, and all publications citedherein are incorporated by reference in their entireties for any and allpurposes.

It is to be appreciated that certain features of the invention whichare, for clarity, described herein in the context of separateembodiments, may also be provided in combination in a single embodiment.Conversely, various features of the invention that are, for brevity,described in the context of a single embodiment, may also be providedseparately or in any subcombination. Further, reference to values statedin ranges includes each and every value within that range.

To fully describe the application of the disclosed methods and systemsto ICP measurement and to describe why pressure in retinal vessels iswell-correlated to ICP, a review of the anatomy and physiology of theeye and surrounding tissues is useful. The optic nerve connects theretinal ganglion cell axons within the eye to the brain and iscompletely surrounded by the subarachnoid space. The subarachnoid spaceis filled with cerebrospinal fluid (CSF), and the pressure of this fluidis equivalent to ICP. The central retinal artery, vein and centralretinal nerve travel through the central region of the optic nerve,converging at the optic nerve head in the back of the eye. As CSFpressure increases, the pressure in the subarachnoid space increases,which exerts an increasing pressure on the optic nerve. This increasedfluid pressure in turn applies a pressure around the central retinalvessels that travel within the optic nerve, causing an increase in bloodpressure in the central retinal vessels proportional to the CSFconstriction pressure.

Changes in ICP are frequently correlated to changes in pupillary reflex.Traditionally, the extent of the pupillary reflex has been subjectiveand determined by waving a flashlight into a patients eye to observe thepupils reactivity and thus the status of the nervous system and brain[the retinal sensory receptors, sensory fibers (optic nerve II), thebrain stem and mid brain, motor fibers (oculomoter nerve III) and thepupillary constrictor muscle in the iris]. In the present invention,changes in constriction and dilatation of pupils in response to lightcan be quantitatively assessed in the same instrument which has thefunctionality of an ODM, tonometer, and ICP monitor. Providing the userwith these multiple neuro-opthalmic measures and data from pupillometryin a virtually simultaneous or sequential manner will simplify, speed upand significantly enhance the available information to assess theneurological status of the patient. It also offers the ability to use asingle device for measuring combinations of ophthalmodynamometry,tonometry, ICP, and pupillometry.

In one aspect, the present disclosure provides methods of estimatingintracranial pressure in a subject. These methods include, inter alia,imaging an intraocular blood vessel while applying a force to asubject's ocular globe so as to at least partially osculate at least aportion of the ocular globe and increase intraocular pressure so as tocollapse an intraocular blood vessel. The force may be applied directlyto the subject's cornea or sclera, but this is not a requirement, asforce may be applied to an eyelid (upper or lower) of the subject so asto indirectly applanate a portion of the ocular globe.

The methods also include estimating, suitably by controllably imagingthe osculated portion of the subject's ocular globe, the intraocularpressure that collapses the intraocular blood vessel; and correlatingthe estimated intraocular pressure that collapses the intraocular bloodvessel to an estimated intracranial pressure of the subject. This may beperformed in an automated fashion, and embodiments where a computercontroller and processor act to controllably apply the osculating forceand collect images of the osculated portion of the eye and of the bloodvessel are considered especially suitable. Embodiments where a computerprocessor correlates the applanated area of the ocular globe to theapplied pressure that collapses the blood vessel are consideredsuitable.

The at least partially osculated portion of the subject's ocular globesuitably includes a portion of the sclera, a portion of the cornea, oreven both. This may be affected by a manually-controlled device or by anautomated or computer-controlled device. The user may suitably osculatethe ocular globe by pressing directly on the ocular globe.Alternatively, the user may press on an eyelid of the subject so as toosculate the ocular globe. The osculation may be effected by a flat-endrod or other shaped device. Ultrasound probes may be used as osculator,as an ultrasound probe may be used to apply force to the eye, and evento image the blood vessel of the eye, in some cases. In someembodiments, the ultrasound probe may be contacted to the eyelid or thecornea of the subject so as to applanate the ocular globe, with theultrasound probe also being used to image the blood vessel in the eye.

In some embodiments, the methods suitably include estimating theintraocular pressure that collapses the intraocular blood vessel bycorrelating one or more images of the osculated portion of the subject'socular globe to the applied force corresponding to the one or moreimages of the osculated portion of the subject's ocular globe. The usermay image the osculated portion of the subject's ocular globe whileapplying a first, reference osculation force. Subsequent to orcontinuous with application of this first reference force, a knownincreasing force is continuously applied while images of the osculatedarea are simultaneously obtained.

Concurrent with obtaining images of the osculated area, the user mayobtain images of the retina in which the central retinal vessels can beobserved. These retinal images may be synchronized with the osculatedarea images and applied force data so that when a collapse of one of thecentral retinal vessels is observed in the retinal images, the osculatedarea and applied force at that moment in time is known.

Knowledge of the osculated area and applied force at that moment allowsthe user to calculate the intraocular pressure at the time of vesselcollapse, and therefore estimate the pressure within the vessel at thetime of collapse. Alternatively, osculated area images and applied forcedata from moments immediately before and/or immediately after the momentof observed retinal vessel collapse may be used to calculate intraocularpressure at the moment of vessel collapse. Other means of measuringintraocular pressure at the moment of collapse can also be utilized inaccordance with the invention. For example, osculating the ocular globeand viewing the retinal vessels, synchronized with transpalpebral,pneumatonometric, or contour tonometry estimates of intraocular pressuremay be used.

Imaging may, as described herein, be effected by one or more imagecollectors. As shown in FIG. 2, for example, a user may collect imagesof the ocular globe and of the collapsed or collapsing blood vessel on asingle image detector. Alternatively, a user may employ one imagedetector to collect an image of the ocular globe and another imagecollector to collect images of the blood vessel or vessels of interest,as illustrated in FIG. 5.

Osculating the ocular globe to elevate and measure intraocular pressureand to view retinal vessels to determine the point of retinal vesselcollapse is one central element that may be accomplished, for example,by sharing optical elements, an imaging axis and imaging sensors asshown in FIGS. 1 and 2 or accomplished using separate optical elements,imaging axes and imaging sensors as shown in FIG. 5 for example. It isunderstood that imaging of the retina may be accomplished in a varietyof optical configurations understood in the art. In the presentinvention and using such configurations, accommodation may be made topermit concurrent applanation of the ocular globe and determination ofintraocular pressure through osculation area and force.

Illustrative FIG. 1 shows an optically clear osculator 135 at the distalend of a device used to applanate the cornea, which also provides anoptical pathway through which the retinal images can be obtained. Inthis embodiment, the central anterior portion of the osculator has aconvex-plano (proximal convex shape-distal plano or flat shape) shape toenhance retinal imaging. It should be understood that an osculator mayhave a plano, convex, concave, a prism, or any combination of surfacesthereof. For example, a osculator may be plano-plano in configuration.Alternatively, an osculator may be a prism-plano. An osculator may alsobe convex-concave. The convex surface or lens compensates for some orall of the refractive power of the cornea lost when the cornea isflattened or applanated. The osculator may have a plano-planoconfiguration or may contain other prismatic corrections to image theoff-axis optic disk, as convex-plano osculators are not a requirement.The retinal vessels observed in the retinal images may be illuminated byambient light or by a provided illumination system. The retinalillumination system can comprise an illumination source that is co-axialwith the optical path and converge at an apex. Alternatively, in oneembodiment the illumination source can comprise multiple off-axisillumination paths.

Estimation of the intraocular pressure at which a central retinal vesselwill collapse may be performed by analyzing synchronized retinal images,osculation surface images and force application data. This estimationmay be performed during or after the ocular globe has been osculated. Insuch an estimate the user may review or inspect the retinal blood vesselimages, the synchronized osculation surface images and the force appliedto the ocular globe to determine the intraocular pressure at the momentof collapse of the intraocular blood vessel. A function can be derivedbased on using the resting IOP as an initial condition and thecalculating the amount of fluid displaced from the anterior chamber asthe cornea is applanated. For example, for an eye with a resting IOP of10 mmHg (millimeters mercury), a 9.8 gram-force to applanate an area of38 square millimeters would result in an IOP estimate of 18 mmHg. With aresting IOP of 15 mmHg, a 12 gram-force to applanate an area of 34square millimeters would result in an IOP estimate of 25 mmHg. Oneexemplary method of estimating IOP (e.g., for applanated areas greaterthan 3.06 mm in diameter) is set forth by Eisenlohr et al., Brit J.Ophthal. (1962) 46, 536).

In some embodiments of the present invention, the methods includeautomated or semi-automated determination of the pressure that collapsesthe intraocular blood vessel. In such embodiments, the user may employan automated image processing algorithm that compares sequential imagesof the intraocular blood vessels to determine the moment in time whencollapse of the central retinal blood vessel occurs, and thereforethrough the synchronized data the osculating force at that moment intime. One or more of the optical density, color, and caliber of thevessels will change upon vessel collapse, and these characteristics aresuitable for automated or manual determination.

Imaging the intraocular blood vessel is suitably accomplished bycollecting an image of the retinal fundus on an image collector.Suitable image collectors include focal plane arrays, such as CCDdevices, CMOS devices, and the like. The focal plane array may be atwo-dimensional array such as those available from Aptina (San Jose,Calif.), or Cypress Semiconductor Corporation (San Jose, Calif.), oreven be a linear array such as those available from Goodrich Corporation(Princeton, N.J.).

The periocular arteries that supply blood to tissues and structures ofthe eye pass through the cerebral spinal fluid (CSF) and are sensitiveto changes in CSF pressure. Systolic and diastolic blood flow velocitiesare subject to a complex auto-regulatory process in which the perioculararteries continue to supply sufficient blood circulation to the eye evenwhen a patient has an elevated ICP. As pressure increases surroundingthe blood circulation to the eye, various blood flow parameters in thecentral retinal and ophthalmic arteries are also affected.

The user may, in some embodiments, obtain Doppler ultrasound informationfrom a periocular blood vessel of the subject to improve the accuracy ofcorrelation between the present invention and invasive measurements ofICP. Periocular blood vessels within the cranium are located within orclose to the eye. Examples include the ophthalmic artery, the centralretinal artery and vein, superior and inferior ophthalmic veins, themiddle cerebral artery, etc. Locating a periocular blood vessel issuitably performed by insonating the vessels that supply the ocularglobe and exit the cranium through the optic canal or cavernous sinus.Auditory and/or visual signals without imaging may also be used toindicate that a vessel has been identified. An example of an auditorysignal may include changes in sound pitch in response to changes inblood flow. An example of a non-imaging visual signal may include alinear LED array that lights successive LED's in response to increasedsensed blood flow.

A variety of blood flow parameters may be used in estimating ICP (see,e.g., U.S. Pat. No. 7,122,007 to Querfurth, incorporated herein byreference in its entirety). Pulsatility index (“PI”), resistivity index(“RI”), systolic velocity, diastolic velocity, and the like are allsuitable velocity indicia for use in the system. PI is considered aparticularly suitable velocity parameter for use in the system. Bloodvelocity in vessels within the cranium is affected by intracranialpressure. Blood velocity, particularly in the arteries, is not constantfor a given intracranial pressure, but varies in relation to the statusof the cardiac cycle. Maximum blood velocity is termed “peak systolicblood velocity”, and corresponds to maximum heart contraction. Minimumblood velocity occurs during the time that the heart is filling withblood (diastole) and is termed “end diastolic blood velocity.”

${PI} = \frac{\left( {{{Peak}\mspace{14mu} {systolic}\mspace{14mu} {velocity}} - {{End}\mspace{14mu} {diastolic}\mspace{14mu} {velocity}}} \right)}{{Mean}\mspace{14mu} {velocity}}$${RI} = \frac{\left( {{{Peak}\mspace{14mu} {systolic}\mspace{14mu} {velocity}} - {{End}\mspace{14mu} {diastolic}\mspace{14mu} {velocity}}} \right)}{{Peak}\mspace{14mu} {systolic}\mspace{14mu} {velocity}}$

As pressure increases surrounding the blood circulation to the eye, theresistivity and pulsatility of the blood flow in the central retinal andophthalmic arteries are also affected.

It has been determined that intracranial pressure can be accuratelyestimated as a function of ophthalmic parameters including centralretinal venous pressure (CRVP) and arterial blood velocity (ABV), whereABV may be assessed using PI, RI, or another blood velocity metric:

ICP=f(CRVP,ABV)

Using sequential measurements from multiple devices one may fit data tothe form ICP=A+Bx. Following the methods and systems described herein,one such functional relationship may be expressed in the formICP=A+Bx+Cy, where x is central retinal vein pressure (CRVP) and y isthe pulsatility index (PI) of the ophthalmic artery. A, B and C arescalars used to fit clinical data and depend on the manner of which theophthalmic parameters are collected. For instance, A and B can beadjusted based on the method of tonometry (e.g., pneumotonometry,transpalpebral, contour tonometry or applanation) and C can be adjustedbased on the periocular vessel chosen for the measurement. By way ofexample and based on clinical experience following the methods andsystems described, one may correlate the CRVP plus the Dopplerultrasound pulsatility index of the ophthalmic artery to ICP using thefollowing regression equation:

${ICP} = {0.294 + {0.735({CRVP})} + {0.735{\left( \frac{1}{PI} \right).}}}$

ICP functions like the one above may be further improved in accuracy byincluding additional independent variables. The embodiments describedherein focus on ophthalmic parameters not previously considered in aunified expression; biomechanical variables including but not limited tooptic disc swelling or other ocular biomechanical properties that areaffected by elevated ICP. These peripapillary ophthalmic parameters canbe incorporated into an independent ophthalmic tissue variable (OT), inunits of stress. Thus:

ICP=f(CRVP,ABV,OT).

In addition, patients in need of a determination of intracranialpressure may, in some cases, also have papilledema, a swelling of theoptic disc that occurs secondary to elevated intracranial pressure.Papilledema develops in a stepwise fashion, and can be tracked bymedical professionals using a widely accepted grading scheme firstproposed by Frisen (Stavern 2007 “Optic Disc Edema” in Seminars inNeurology, vol. 27, no. 3, pages 233-243, 2007); and S. Echegaray,“Automated Analysis of Optic Nerve Images for Detection and Staging ofPapilledema” (in Investigative Ophthalmology and Visual Science, vol.52, no. 10, pages 7470-7478, 2011). The Modified Frisén Scale classifiespapilledema into six grades from 0 (normal) to 5 (severe). Each grade ischaracterized by a set of objective, visual features observed on theoptic disc and peripapillary retina. A device that captures images ofthe optic disc and surrounding peripapillary retina and classifiespapilledema using the Frisén grading method will not only provide theability to objectively assess papilledema severity, but will be able touse the level of papilledema severity as an input to an algorithm formore accurately determining ICP. Various implications and assessment ofICP are discussed in U.S. patent application Ser. No. 12/959,821 (filedDec. 3, 2010), the entirety of which is incorporated herein by referencefor all purposes.

Another method of assessing papilledema severity in order to moreaccurately determine ICP is to use ocular coherence tomography (OCT) tomeasure peripapillary retinal nerve fiber layer (RNFL) thickness.Swelling of the peripapillary retina due to elevation in ICP will causean increase in the RNFL thickness. Therefore, a technique that canprovide RNFL thickness can be used to improve an algorithm fordetermining ICP.

For example, one such variable, the severity of papilledema present insome patients with elevated ICP, may be used to modify the aboveequation. Papilledema and its associated swelling of the tissues of theoptic disc and surrounding retina due to an increase in axoplasmic fluidsurrounding the axons, may cause an increase in bulk tissue pressure(P_(BT)). This bulk tissue pressure will contribute (along with thecerebrospinal fluid pressure, or ICP) to the overall pressure beingapplied to the central retinal vein. The magnitude of P_(BT) iscorrelated with the severity of papilledema, and may therefore correlatewith the papilledema grade from the modified Frisén scale (MFS). In thiscase OT is a function of P_(BT) or, OT=f(P_(BT)). One may use MFS toobtain OT or, OT=f(MFS).

Another method of assessing papilledema (and therefore assessing P_(BT))is to use OCT to measure peripapillary RNFL thickness. OCT is anon-invasive technique that provides cross-sectional images of the RNFLand provides absolute measurements of the fiber layer thickness.Increases in the thickness of this fiber layer are directly correlatedto the severity of papilledema, and so OT=f(RNFL). Incorporating the OTcomponent into the ICP functional equation above yields:

${{ICP} = {A + {B({CRVP})} + {C\left( \frac{1}{PI} \right)} - {D({OT})}}},$

where A is directly proportional to the Frisén Scale papilledema grade.As set forth above, a user may estimate intracranial pressure by basingthat estimate at least in part on an assessment of the degree, of any,of papilledema that may be present in the subject. The papilledemaassessment is suitably based on the Frisén or modified Frisén scale. Theassessment may be performed in an automated fashion. One such approachto an automated assessment of papilledema presence is set forth by S.Echegarry et al. Alternatively, the assessment of papilledema may bemade by way of optical coherent tomography (OCT), as described herein.

Accordingly, as set forth above, the present disclosure provides methodsof assessing the intracranial pressure of a subject. These methodsinclude, inter alia, estimating intracranial pressure by combining anassessment of the level of papilledema, if any, present in the subjectwith one or more of a blood velocity of the subject, a blood vesselpressure of the subject, a tissue thickness of the subject, or anycombination thereof. The tissue thickness may, for example, be thethickness of the retinal nerve fiber layer, the thickness of theprelaminar optic nerve head tissue, or some combination of these. Theblood velocity may be a systolic velocity, a diastolic velocity, or anycombination thereof, such as the PI and RI indices described herein. Thepapilledema level comprises a Frisén scale score of the papilledema. Theassessment of the papilledema level, the tissue thickness, or both, isbased on optical coherent tomography (OCT) or other methods to measureperipapillary RNFL thickness, prelaminar optic nerve head tissuethickness, or other ocular tissues.

The present disclosure also provides systems for measuring intracranialpressure in a subject. These systems suitably include a portion (the“osculating cap”) to controllably at least partially osculate (i.e., atleast partially flatten or curve match) at least a portion of the ocularglobe of a subject's eye. This osculation may be effected by contactingthe eye with an osculation surface or even by an ophthalmic component,which may also be referred to as the osculator. It should be understoodthat the osculation may be effected by applying a force to, e.g., theeyelid of the subject, the cornea or sclera of the subject, or two ormore of the foregoing.

The systems suitably include at least a first image collector configuredto collect light from an intraocular blood vessel of the subject's eye,and a retinal illumination train that may be configured to direct lightthrough an ophthalmic component (which may be referred to as anosculating cap) to the intraocular blood vessel of the subject's eye andto direct light reflected from the intraocular blood vessel to the imagecollector and a microprocessor. An image collector may be configured toview the intraocular blood vessel in the absence of a systemillumination train. For example, a sensitive, low-light image sensor maybe used to collect images illuminated by ambient light. Alternatively,an infrared sensitive image sensor may also be used. The osculating cap(as one illustrative ophthalmic component) may be sterile and removablyaffixed or otherwise engage with an optical module (which may bereferred to collectively as the optical train). The optical module andmotion of the osculator may be a motor-controlled as describe below, butmay also be manually controlled and advanced.

The system of the present disclosure can be configured using one or morefocal plane array image sensors for imaging the retina and the osculatedportion of the ocular globe of the subject. In one embodiment a singleimage sensor is configured to collect images from both the retina andthe interface between the cornea and an osculation area (which may bereferred to as “corneal imaging” or “corneal image”). The images can becollected simultaneously or in rapid and repeating succession. A singleimage sensor system may be configured into a light weight, compactsystem. In a single sensor system the image sensor may be required tocontinuously collect high-speed images for applanation analysis andhigh-resolution images of retinal vessel analysis. Alternatively, rapidsequential image collection may be utilized that require the singlesensor to sequentially change from high-speed low-resolution tolow-speed high-resolution data collection. Presently, sensors operatingin either configuration are suitable but relatively expensive.

In another embodiment, two separate arrays may be utilized for retinaland corneal image capture to overcome the limitations of a single sensorsystem. A system has been effectively constructed using a first sensorto collect images from the retina and a second sensor to collect imagesfrom the osculated portion of the ocular globe.

The motion of the optical train may be manually-controlled.Alternatively, the optical train may be computer-controlled. Anysuitable method of advancing the osculator onto the surface of theocular globe can be used. Electromagnetically driven mechanisms, e.g. avoice coil motor, were successfully clinically tested. However, othermotion control mechanisms such as conventional and stepper motors,pneumatic actuators and the like may also be utilized.Electromagnetically driven mechanisms, including voice coil motors, haveadded advantages. In addition to inducing controllable displacement ofthe osculator, they also produce an electrical indication of the forcebeing exerted. Further, inflatable accordion-style osculating caps maybe used.

The osculator may be of any material compatible with the cornea such aspolycarbonate, polymethyl methacrylate (PMMA), polyethylene (e.g., LDPE)or even glass. Transparent materials are especially suitable for theosculator and ophthalmic components. The osculator diameter can rangefrom about under 4 mm to over 15 mm. One parameter that may at leastpartially determine the osculator size is the degree to which the ocularglobe is osculated. For an adult cornea, a convenient size is 10 mm. Theosculator may suitably be transparent, although transparency is not arequirement. The osculator may be translucent or opaque as well, whichmay be suitable for use when the applanation portion (e.g., ophthalmiccomponent or oscualting cap) contacts the eyelid or sclera. In someembodiments, the osculator includes a lens, prism, or both formed in aplano body.

The osculating cap may have an engagement portion configured to engagewith an optical module suitably movable for contact with the ocularglobe. The osculating cap is suitably constructed to be sterile andremovably affixed to the optical module and able to snap on, screw onto,be magnetically held or otherwise affixed thereto. The cap may bereusable or disposable.

The osculating cap may bear one or more indicia. These indicia (whichmay be present in the form of letters, numbers, barcodes, or evenelectronic form) may be used to identify the applanation cap in terms ofclinical use, size, shape, or other characteristic. For example, aparticular index may convey that the osculating cap bearing the index issized for use in pediatric patients. Since a child's ocular globe issmaller than an adult's, use of an appropriate osculating cap mayeliminate the need for focus adjustments and associated mechanical andoptical complexity. Further, it can notify system electronics of therequisite operating parameters (maximum force, etc.) that can be exertedon the child's eye.

The disclosed methods and systems may be used for indications other thantraumatic head injury. For example, when measuring resting intraocularpressure in patients with glaucoma or ocular hypertension, one would notrequire an osculating cap incorporating retinal imaging compensationoptics. The indicia will notify the system parameters of the device'sintended use and settings and, in this case, appropriately limit theosculation force. In this manner, a system may include a set of one ormore osculating caps so as to accommodate subjects that are themselvesdifferent. For example, an emergency medical team might maintain a setor kit of multiple caps so as to accommodate patients of various sizes.The systems and methods may also be configured obtain a translaminarpressure (i.e., the pressure difference between IOP and ICP that isapplied to the optic nerve head), which may be used as a more accurateindicator of glaucoma susceptibility than IOP alone. Further yet, thesystem can be configured for measuring pupillary reflex.

In some embodiments, the ophthalmic component is configured so as todirect light reflected from the intraocular blood vessel to the firstimage collector. The ophthalmic component may also be configured todirect an image of the osculation interface between the ophthalmiccomponent and an osculated region of the ocular globe to the first imagecollector. The system may be configured to direct an image of thecollapsing or collapsed blood vessel and an image of the osculationinterface to a single image collector, as illustrated in FIG. 2. Inother embodiments, the images are directed to separate image collectors,as illustrated in FIG. 5

In some embodiments, the system is capable of self-configuring inresponse to indicia on the osculating cap. For example, the system mayadjust the osculator, the image collector, or even the illuminationtrain in response to one or more indicia present on the cap. As oneexample, an auto-focus motor could pre-adjust the location of theimaging sensor prior to the beginning of data collection, correspondingto the patient's eye size (as indicated by the choice of osculatingcap).

The system may be configured such that during operation it concurrentlyapplies a force to the subject's ocular globe and collects, from animage collector, images from at least one of an intraocular blood vesselof a subject's eye and an interface between the osculation area and theocular globe of the subject's eye. Applanation of the cornea andsimultaneous visualization of the retina has been found to be aparticularly convenient configuration. In this configuration, osculationdoes not cause lateral movement of the ocular globe or distort the viewof retinal vessels. In addition, all measurements are made along thesame axis. In certain embodiments, the system is configured to, duringoperation, concurrently osculating at least a portion of the subject'socular globe and collect, on the first image collector, light reflectedfrom the intraocular blood vessel of the subject's eye.

An illumination train may, in some embodiments, include one or morelight sources such as a light-emitting diode (LED), an incandescentlamp, an electroluminescent light source, and the like. In someembodiments and as most clearly shown in FIG. 6 in conjunction withFIGS. 7 and 8, the illumination train includes light-emitting diodesarranged in a circular or ring configuration. It should be understoodthat light emitted from the light sources may have a wavelength in thevisible light range (wavelength approximately 400 nm to 700 nm), but mayalso be infrared light (wavelength approximately 700 nm to over 1,200nm). Thus, the term “light” as used herein shall be understood to meanenergy in the visible and near infrared regions of the electromagneticspectrum.

Systems may also include a fixation illuminator configured so as toprovide a reference point for the subject to align the ocular globe.Such illuminators may be a light source upon which the subject focuseswhile the system is operating on the subject. In this way, the subject'seye is stabilized and maintains a consistent orientation duringoperation of the device.

Systems may further include a Doppler instrument configured so as tocollect ultrasound data from a periocular blood vessel of the subject.Examples of periocular blood vessels include the ophthalmic artery, thecentral retinal artery and vein, the lacrimal artery, posterior ciliaryarteries, superior and inferior ophthalmic veins, and middle cerebralartery. Ophthalmic artery insonation requires penetration ofapproximately 40 to 50 mm. For this amount of tissue penetration, anultrasound probe of between 7 MHz and 10 MHz is preferred. Locating aperiocular blood vessel is suitably performed by using a color Dopplerultrasound imaging system. Examples of such devices are commerciallyavailable from General Electric (www.ge.com) and Philips(www.philips.com). Alternatively, a non-imaging Doppler ultrasoundsystem with auditory and/or visual feedback signals locate a periocularblood vessel by scanning the anatomical volume of interest using alinear probe can be used. One such device is an ultrasound transducermanufactured by Multigon Industries. The Doppler sensor may beadjustably fixed to the body of the invention as shown in FIG. 1 or maybe separately held.

The systems may, in some embodiments, be configured so as to be capableof assessing the degree, if any, of papilledema present in the subject.In one illustrative embodiment, the system is configured to obtain oneor more images of the fundus of the subject and compare at least one ofthese images to a library image of a fundus, and generate a papilledemagrade for the subject. The system may include a processor configured toestimate intracranial pressure of the subject based on one or moreimages of the at least partially osculated area of the subject's eye andone or more images of the intraocular blood vessel of the subject's eye.The papilledema assessment method of S. Echegaray et al., is consideredespecially suitable for application to the disclosed systems andmethods.

The systems in the present disclosure may include an osculating capconfigured to controllably contact an applanation portion (which mayalso be referred to as an ophthalmic component, an osculator orosculation area) to the ocular globe of a subject's eye. Suitableosculators and osculating caps are described elsewhere herein. Thesystems may also include an image collector configured to collect lightreflected from an intraocular blood vessel of the subject's eye. Thesystem may also include an illumination train configured to direct lightthrough the osculator to the intraocular blood vessel of the subject'seye and to direct light reflected from the intraocular blood vessel tothe image collector. During operation, the system may record retinalfundus images and score features of the optic disc using imageprocessing algorithms known to those of skill in the art. The system maybe configured to compare feature scores to a database of images for thepurpose of grading papilledema according the Modified Frisén scale. Thesystem may be configured to output a Frisén scale score of papilledemapaired with an image of the optic disc for purposes of trackingpapilledema progression. The system may thus assess a subject'spapilledema and assess the patient's condition over time. In someconfigurations, the system generates a papilledema score in an automatedfashion. The systems may be configured to, during operation, recordretinal fundus images, score features of the optic disc using imageprocessing algorithms, or both. The systems may also be configured tocompare feature scores to a database of images for so as to grade thepurpose of grading papilledma, if present, according the Modified FrisénScale.

Further disclosure is now made by reference to the attached figures.

FIG. 1 illustrates a cutaway view of an exemplary intracranial pressuremeasuring system according to the present disclosure. As shown, ICPmeasuring system 100 suitably includes a movable optical module 102 thatengages with the osculator 135. In this embodiment, Osculator 135 has aflat applanation surface. A motion control module 104 (not shown) maymodulate the motion of the optical module 102 and the osculator 135.Electronics module 108 contains units adapted to control and modulatethe device's actions and operations. Optical module 102 collects retinalimages simultaneously with electronic module 108 collecting force andposition data from force transducer 105 and position sensor 106,respectively. Motion of optical module 102 to applanate a portion ofocular globe 15 may be manual or automatic. Automatic motion of theoptical module is suitably controlled by motor 111, force transducer 105and position sensor 106. Optical module 102 suitably translates in arange of several centimeters, e.g., by 0.5, 1, 2, 3, 4, or even 5.During operation and upon contact with the cornea, force transducer 105limits the force to appropriately safe levels of intraocular pressureand the portion of ocular globe 15 osculated. Position sensor 106 maylimit translation to under approximately 4 mm (subject to the size ofthe subject's eye) so as not to harm the subject. Following datacollection, which nominally takes approximately 5 to 10 seconds, opticalmodule 102 automatically retracts. If desired by the user, a scrollwheel, lever, slide or the like may be used to review the osculationforce and the images of the retina on display 112 collected duringactuation so as to identify the instant of vessel collapse. Theidentification of the instant of vessel collapse may also be automatic.

The sensor used to determine force applied to the ocular globe may beany form of force transducer, including one or more of electricalresistance, foil, semiconductor or thin film strain gauges and otherforce measurement devices. Force transducer 105 can be located in anyposition in ICP measuring system 100 that will provide a signalproportional to the force applied to the ocular globe. As shown, forcetransducer 105 is positioned between motor 111 and the movable opticalmodule 102. The determination of force by sensing a change in thecurrent from a voice coil motor 111 drive is of particular value due touse of a single device to drive the optical module and sensitivelymeasure the forces exerted. Locating a force transducer in closeproximity to osculator 135 may be advantageous. Position sensor 106provides information on the absolute position and velocity of theosculating cap. Several position sensors are readily available for thisapplication. Hall effect sensors have been found to be suitably small,inexpensive and accurate. However, other sensors including but notlimited to inductive sensors, linear variable differential transformer(LVDT) sensors, etc. may be used. ICP measurement system 100 may beequipped with a head support (not shown) so as to stabilize the positionof the device on the subject. For the convenience of the operator andsafety of the subject, optical module 102 and osculator 135 may bepositioned such that osculator 135 will not touch the subject's ocularglobe until the system is stabilized on the subject and determinedappropriate by the operator. Batteries 109 may be used to power thedevice. The device may also run off of household or commercialelectrical lines. A trigger 110 may be used to actuate the device, e.g.,to advance the osculator, or take one or more images, or to effect oneor more other action

FIG. 12 depicts an exemplary flow diagram of the operation of anintracranial pressure measuring system. Upon powering on the apparatus(“Start”), the system senses the presence of an osculating cap and turnson the video monitor. System electronics setup the system perinformation provided in the selected cap's indicia. After placement ofthe system over the subject's eye (not shown in flow diagram), theoperator depresses a trigger 110 to simultaneously advance the opticalmodule and initiate recording of data from the five sensors. A positionsensor is monitored to determine the optical modules location andvelocity. A primary force sensor senses the force required to advancethe cap and optical module as detect the increase in force resultingfrom contact with the ocular globe. A secondary force sensor ismonitored to insure that the force measured by the primary force sensoris within safe limits; else the optical module is withdrawn. A sequenceof movements of the optical module is followed in accordance with thecap indicia information. Once the sequence is completed, the opticalmodule is withdrawn from the cornea, sensor monitoring processes cease,data is analyzed and the value of ICP is displayed.

The embodiment shown in FIG. 1 also illustrates Doppler ultrasoundtransducer 115 suitably mounted on transducer pivot arm 116 to permitcontact of Doppler transducer 115 in the periocular region and orientedtowards the ophthalmic artery. A signal such as an auditory signalvaries in pitch and volume that may help the operator aim the probe inthe correct orientation. The Doppler device may be constantly collectingDoppler ultrasound data using either an auditory or visual feedbacksignal. Once transducer 115 is correctly positioned, pulsatility datamay be collected and averaged over at least three heart cycles.

FIG. 2 depicts an exemplary optical configuration of a single imagesensor system 10 according to the present disclosure. In such an ICPmeasurement system, a first image may be collected of optic disc region32 of retina 30 and focused on a first portion of retina/cornea imagesensor 50 so as to distinguish a collapsed blood vessel such as thecentral retinal vein. A second image may be collected indicative of thedegree of applanation of the ocular globe and focused on a secondportion of retina/cornea image sensor 50. Exemplary retinal imaging path55 is also shown, as is corneal imaging path 65.

A portion of ocular globe 15 is flattened by osculator 35. In theembodiment shown, the portion of ocular globe 15 that is osculated iscornea 20. The distal surface of osculator 35 is shown as a flat orplano surface and proximal side is shown as a convex surface (referredto as “osculator lens 36”). Light reflected from retina 30 passesthrough ocular lens 26, flattened cornea 20, osculator 35 and objectivelens 40. Objective lens 40 may be comprised of one or more lenses. Thelight reflected from retina 30 is then reflected by dichroic beamsplitter 45 onto retina/cornea image sensor 50. Light from retina 30 maybe reflected from an external source of illumination (not shown). In oneexemplary embodiment, retina 30 is illuminated using visible lightsource at 565 nm. Any number of dichroic beam splitter 45 could beutilized such as, for example purposes only, a 580 nm single-edgelong-pass dichroic beam splitter that reflects >95% of wavelengths inthe range of 350 nm to 570 nm and transmits 93% of wavelengths from 591nm to >950 nm (Semrock, Inc., Rochester, N.Y.). Alternatively, lightfrom retina 30 may be infrared energy emitted as a result of heat fromretina.

Osculation of cornea 20 by osculator 35 causes flattening of the corneaand a resulting change in the pattern and intensity of light reflectedby the cornea onto retina/cornea sensor 50. The force required toflatten cornea 20 increases with increased osculation. It is well knownthat by measuring the force required to osculate (applanate) the corneato a known area (typically 3.06 mm in diameter) one may estimate theresting intraocular pressure. So-called corneal applanation tonometryhas been one standard means of measuring intraocular pressure forscreening and routine management of patients with ocular hypertensionand glaucoma.

In traditional applanation tonometry, corneal flattening substantiallyunder 3.06 mm results in loss of measurement accuracy due to effects ofcorneal rigidity and tear-film complications. Flat osculation(applanation) of the cornea to an area substantially greater than 3.06mm decreases the accuracy of the measurement to greater than acceptednorms of +/−0.5 mmHg. This is due to an induced increase in thepatient's intraocular pressure. As a result, applanating the corneabeyond 3.06 mm is generally contraindicated, although the 3.06 mmapplanation area is not a requirement or limit. In the presentinvention, the operator suitably elevates intraocular pressure so as tointentionally generate intraocular pressure sufficient to collapse theretinal vasculature. Estimating IOP for osculation areas greater than3.06 mm requires modeling of the biomechanics of the cornea to determinepressure as a function of force and area. A function can be derivedbased on using the resting IOP as an initial condition and thecalculating the amount of fluid displaced from the anterior chamber asthe cornea is osculated. One exemplary method of estimating IOP (e.g.,for applanated areas greater than 3.06 mm in diameter is set forth byEisenlohr et al., Brit J. Ophthal. (1962) 46, 536).

Flattened cornea 20 can be visualized and the area of osculationdetermined by imaging cornea-osculator interface 34 using an imagesensor illuminated by any wavelength sensitive to the image sensor.However, it is preferable to select a wavelength different from thatused to illuminate retina 30. In the example above using the describedbeam splitter and retina illumination (not shown), cornea illuminationsource (not shown) was selected to be an 850 nm LED. It is preferable,but not a requirement, that the retina be illuminated by 540 nm to 570nm green light. Such wavelengths provide excellent contrast and enhancevisibility of the retinal vasculature. Light reflected by flattenedcornea 20 passes through osculator 35, objective lens 40 and dichroicbeam splitter 45. Bending mirrors 60 positions reflected cornea light topass through corneal imaging lens assembly 62 and corneal portion (left)of aperture 67 and focus the corneal image on retina/cornea image sensor50. Aperture 67 serves to reduce unwanted vignetting and backscatter ofillumination from the system optics and anatomical structures such asthe lens and cornea.

FIG. 3 shows the results of illuminating osculation interface 34 of aporcine cornea using near infrared light. However, similar results areobtained using visible illumination light. A portion of the illuminationlight reaching osculator interface 34 will be reflected back and bevisible by retina-cornea image sensor 50. Indicia 70 are also shown. Thereflection is the result of the differences in the index of refractionbetween the osculator and either ambient air or aqueous from thesubject's tear film. When the osculator is in contact with the cornea,the contacted portion of the illumination light is transmitted throughthe osculator and will appear darker when viewed by the image sensor asshown as applanation area 74. Thus, the darker circle will grow in sizeas greater force is exerted on the cornea. In this example, the pressurein the pig's eye was initially set at 10 mmHg with a manometer.Incremental increases in force on the ocular globe will result inincremental increases in intraocular pressure above the initially set 10mmHg. Maximum osculation area 72 is shown as a circular line as areference to the user. In this example and upon contact of the osculatorwith the pig's eye, the results are as follows:

Diameter/Area Force Measured pressure FIG. 3A 0.91 mm/0.007 cm² 0.50 gF— FIG. 3B 3.54 mm/0.098 cm² 1.06 gF 10.8 mmHg FIG. 3C 6.31 mm/0.313 cm²3.55 gF 11.3 mmHg

FIG. 4 shows an image taken by a single retina-cornea image sensorsystem similar to that shown in FIG. 2. The larger retinal fundus 76 andsmaller corneal applanation area 74 were taken of a rabbit. In the imageshown, a 1.3 megapixel (1280H×1024V) CMOS sensor was used. However, theselection of sensor depends upon the design of the optical train, theillumination, the desired field of view, the frame rate, etc. A personof skill in the art will select appropriate optical and opto-mechanialelements to meet the desired system specifications. A large field ofview and high-resolution image is beneficial for retinal imaging. Thelarge retinal field of view allows for more rapid identification of theoptic disk. Higher resolution also permits the ability to electronicallyselect the area of interest and maintain sufficient resolution toobserve vessel collapse. In this illustrative example, satisfactoryretinal images were obtained using approximately 1024×1024 px field. Incontrast, determination of corneal osculation area was effectivelyobtained using a 256×256 px field.

FIG. 5 depicts an exemplary dual sensor system 150 according to thepresent invention. This system provides retinal illumination andimaging, corneal illumination and imaging, and a fixation point asdescribed below.

For convenience, the retinal illumination aspect of the system 150 isdescribed first and is highlighted in FIG. 6. While reference to retinalillumination is used herein, it should be understood that reference tothe ‘retina’ or ‘retinal’ is to include blood vessels leading to andfrom the retina and more particularly the central retinal artery andvein.

Retinal illumination light source 160 may be a ring of light sourcesincluding for example light emitting diodes (LED's) that emit lightalong path 157 (one LED illustrated for simplicity of the explanationand shown as a dotted line). Retinal illumination light 158 is reflectedby dichroic beam splitter 154, passes through and is focused byobjective lens 153 and is incident on osculator 35. As shown in FIG. 6and in cross-section A-A′ in FIG. 7, retinal illumination light 158 isfocused and forms a circular illumination pattern 161 on osculator 35peripheral to convex shaped cap lens 36. Cap lens 36 serves tocompensate for the refractive power of the cornea lost due to osculating(flattening) cornea 20. Retinal illumination light 158 diverges andforms illumination pattern 161 as it passes through pupil formed by iris28. Section B-B′ in FIG. 6 shown in cross section in FIG. 8, illustratesthe relative size of retinal illumination pattern 161 in the plane ofiris 22. A constricted iris may vignette a portion of the light, yetprovide sufficient illumination to image retina 30 on retina imagesensor 170 through an un-dilated, 2.4 mm pupil. However, adequateillumination through smaller diameter pupils is also possible. In thisembodiment and as shown in FIGS. 6, 7 and 8, illuminating the retinathrough illumination path 157 peripheral to cap lens 36 and centralpupil 24, obviates the illumination path being coaxial with retinaimaging path 155 that is positioned along the central optical axis ofocular globe 15. The sclera is shown but not labeled. However, in thisconfiguration, both illumination and imaging paths share objective lens153. As a result this configuration minimizes or eliminates illuminationlight reflected back to retina image sensor 170 from objective lens 153,osculator 35, cornea 20 and ocular lens 26. Various image stops orapertures such as retinal image aperture 162 may be added to furtherreduce stray light from entering retina image sensor 170. One or morefocusing lenses 165 may be present to adjust retinal or other lighting.Corneal focusing lens 210 may also be present.

There are numerous techniques known in the art to illuminate the retinawith light entering the eye through the central pupil. For example atotal reflecting mirror with an aperture positioned along theillumination axis may be used in place of dichroic beam splitter 154.This is shown in FIG. 11 as aperture 146 in aperture mirror 145. In thisconfiguration a ring of illumination light is created thereby minimizingreflections back to the retinal image sensor.

FIG. 5 shows a scheme for illuminating and imaging osculation interface34 along the central axis of the ocular globe and sharing objective lens153. Cornea illumination source 220 light passes through dichroic beamsplitters 205 and 235. Field lens 200 focuses illumination source lightto an apex in proximity to dichroic beam splitter 154. Illuminationlight is then collimated by objective lens 153 onto osculator 35 asbetter shown in FIG. 9A illustrating cornea illumination rays 223. Thecollimated illumination light is reflected by osculator 35 back todichroic beam splitter 205 and corneal focusing lens 210, aperture 212onto corneal image sensor 215. Retinal image axis 155 is shown. Corneaillumination path 222 is shown, as well. Fixation light source 230 isalso shown.

As used in one illustrative corneal applanation imaging system,osculator 35 is flat plane of PMMA with a very small, 2 mm in diameterlens 36. The incident illumination light will be normal to flat plane ofosculator 35. Therefore, the reflectance, R, from each surface, proximaland distal, with a refractive index n₀ of air=1 and a refractive indexn₁ of PMMA=1.492, is given by

$R_{P} = {\left\lbrack \frac{\left( {n_{0} - n_{1}} \right)}{\left( {n_{0} + n_{1}} \right)} \right\rbrack^{2}.}$

Therefore, 3.9% of the incident light is reflected from the proximalsurface of the cap and 3.9% from the distal surface where the cap is notosculating the cornea. When the distal surface of osculator 15 iscontacting cornea 20 having an index of refraction n_(C)=1.33, thedistal surface will reflect

$R_{D} = {\left\lbrack \frac{\left( {n_{1} - n_{C}} \right)}{\left( {n_{1} + n_{C}} \right)} \right\rbrack^{2} = {0.3{\%.}}}$

As a result, the osculated surface of osculator 35 cornea will reflect3.9%+0.3% or 4.2% of the incident light and the non-applanated area willreflect 3.9%+3.9% or 7.8%. Thus cornea image sensor 215 will show analmost 2:1 contrast ratio of osculated to non-osculated areas oncontact. FIG. 9B illustrates an osculated area using collimated light.In this example, darker osculated area 177 has a grey value ofapproximately 36 and is surrounded by lighter maximum osculation area176 having a grey value of approximately 64. 175 represents anapplanation image.

FIG. 10 depicts various plano distal end configurations of the osculatorthat are within the scope of the present disclosure. Alterations in theproximal refractive surface of an osculator provide a host of opticaldesign options. For example, FIG. 10A shows the cornea of ocular globe15 being applanated by plano-plano osculator 35A. As shown, the functionof the cap is solely to applanate the cornea. Upon applanation, thepressure in the eye will be elevated and there will be complete loss ofthe refractive power by the cornea. Conventional fundus cameras aredependent on corneal refractive power to view the retina. As a resultplano-plano osculator 35A eliminates use of such camera to view theretina. Further, such cameras have no means to simultaneously view thecornea.

The configuration of the system shown in FIG. 5 and highlighted in FIGS.6 and 9A overcome the limitations of a conventional fundus camera whileproviding a path for simultaneous imaging of the cornea 20. Such aconfiguration will permit viewing the retina along the optical axis ofthe eye centered on the fovea. The optic disc, from which the opticnerve and central retinal artery and vein enter the retina, is locatedapproximately 3 mm nasal and 1 mm superior to the fovea.

FIG. 10B illustrates osculator 35B, which is similar to flat Osculationcap 35A but has a prismatic element permitting a shift in the image ofthe retina. This may permit viewing the retina with the system alignedalong the optical axis of the eye, but centered on the optic disc. FIGS.10 C, D and E show osculators 35C, 35D and 35E with lenses 36C, 36D and36E respectively. These lenses have suitably positive (convex) surfaceson the proximal surface to replace some or all of the optical power ofthe cornea lost during applanation. The configuration and size of theosculation cap and osculator lens is chosen in concert with the rest ofthe optical module. Three representative optical module configurationsare illustrated herein and are not to be viewed as limiting. Otheroptical module configurations and osculator can be designed within theteaching and spirit of the invention by one of skill in the art.

As stated, the osculator may be of any material compatible with thecornea such as polycarbonate, polymethyl methacrylate (PMMA) or evenglass. The osculator diameter can range from about under 4 mm to over 15mm.

The parameter that determines the osculator diameter is the degree ofocular globe osculation. For osculating an adult cornea, a convenientsize is 10 mm. This diameter does not include the area for handling orconveniently mounting the osculator to the osculating cap.

In another embodiment of the disclosed invention, a conventional opticalconfiguration for viewing the retinal fundus is used that does not sharethe optical path for viewing osculation area of the ocular globe. Whilecorneal osculation techniques for collapsing the retinal vessels anddetermination of intraocular pressure is one preferred embodiment, it isunderstood that osculation may be accomplished by osculating of thesclera as well. However, any means of osculation can be used that can beconfigured to permit a view of the blood vessels within the optic diskand determine intraocular pressure. Suitable methods may include but notbe limited to corneal applanation tonometry, pneumotonometry (alsoreferred to a ‘air-puff tonometry”), electronic indentation tonometry,transpalpebral (through the eyelid) tonometry, and the like.

FIG. 11 depicts an exemplary embodiment based on use of a retinal fundusviewing system that does not share an optical path with the path usedfor measuring osculation area. Several retinal imaging and illuminationconfigurations are well known in the art, one of which is shown in thisembodiment. Osculator 135 is positioned to osculate the cornea and formosculation interface 34. Osculation interface 34 is preferably flat butmay be shaped to accommodate placement on the cornea and modificationsin the intraocular pressure measuring scheme. As shown in this figure,retinal illumination source 120 emits light along retina illuminationpath 126, which light is directed by lens or lenses 122 and is reflectedby apertured mirror 145. Apertured mirror 145 has aperture 146positioned along retinal imaging path 121. Aperture 146 permits anun-obscured optical path for imaging the retina. Further, it does notreflect retinal illumination along the central axis of imaging path 121,and as a result it reduces or eliminates light reflected back towardretinal imaging sensor 124. Retinal illumination is transmitted throughand focused by osculator lens 136, passes through pupil 24 and suitablyreflects from one or more intraocular blood vessels of retina 30.Osculator lens 136 is a convex surface on proximal side of osculator 135designed to replace some or all of the refractive power of the corneaduring applanation.

Light reflected from retina 30 passes through pupil 24 and osculator 135and is focused by osculator lens 136 to an apex at or near aperture 146.Reflected light is then focused by retinal focusing lens or lenses 140onto retina image sensor 124.

An exemplary cornea osculation area measurement scheme is also shown inFIG. 11. Corneal illumination source 125 projects illumination light byway of corneal illumination lens 127 to osculation interface 34. Asdescribed herein and as a result of changes in the index of refractionat the cornea and osculating cap interface, the pattern of light atosculation interface 34 changes as a function of the force applied andresulting degree of applanation of the cornea by osculator 135. Thepattern of reflection and resulting intensity of illumination light fromthe osculation interface 34 is focused by cornea imaging lens 129 ontocornea image sensor 131. Thus, ICP measuring system 118 is suitable tosimultaneously image the degree of osculation by osculator 135 on thecornea and, image blood vessels in the optic disc of the retina. Imagingaxis 121 is also shown. An imaging aperture (not labeled) may be presentin communication with the image sensor 124.

The disclosed systems are not limited to the imaging or illuminationarrangements shown in the figures. In one of several variations, lightfrom the illumination source 120 may be one or more LED's configured topass through an axicon lens (not shown) forming a ring of light directedby a dichroic beam splitter to osculator 135.

The conventional lenses in the ICP measurement system have beendiscussed herein. However, such lenses can be replaced using similarlyfunctioning optical elements including diffractive lenses, holographicoptical elements, graded index lenses and hybrid optical elements.

The present disclosure provides additional methods and related systemsand devices for increasing pressure in the eye. These will now bedescribed in additional detail.

In one aspect, the present disclosure provides ophthalmic components.These components suitably include a body having an osculating surfaceadapted to osculate a subject's optical globe, with the body beingadapted to engage with an instrument.

It should be understood that the component may osculate with a subject'seyelid, cornea, or sclera. Corneal osculation is considered especiallyfavorable, but is not required.

The osculating surface may be flat, as shown in FIG. 13A. Alternatively,the osculating surface may be characterized as being a concave opticalsurface that has a radius of curvature, as shown in FIG. 13B. The radiusof curvature may, in some embodiments, be greater than the radius ofcurvature of a subject's ocular globe, e.g., the subject's cornea. Sucha radius of curvature may be greater than about 7 mm or even greaterthan about 8 mm. The surface need not necessarily have a constantcurvature; i.e., the surface may include a flat portion and a curvedportion, or have a curvature that varies in some fashion across thesurface. The osculating surface may be a rigid material, such as PMMA orother polymers.

Alternatively, the osculating surface maybe flexible or even deformable,as shown in FIG. 13D. The component may be configured such that itdefines an enclosed control volume in mechanical communication with theosculating surface, as shown in FIG. 13C and FIG. 13D. The controlvolume is, as shown in FIG. 13D (and as described elsewhere herein),configured to be pressurized while in contact with a subject's ocularglobe. In one approach, a component having such a control volume ismaintained against the ocular globe (e.g., cornea) of the subject, andthe control volume is then pressurized, the pressure in turn exerting apressure against the cornea, which pressure may be increased so as tocollapse an intraocular blood vessel (e.g., a retinal vein). The usermay then use that collapsive pressure as an estimate (or in arriving atan estimate) of the intracranial pressure of the subject. Furtherdescription of this application is provided elsewhere herein.

As shown in FIG. 13C and FIG. 13D, the disclosed components may includea passage or passages that place the control volume into fluidcommunication with the environment exterior to the control volume. Thispassage may be an aperture formed in the component. The passage may alsocomprise a tap, tube, or other protrusion from the component. Apressurizing unit (e.g., a syringe pump or other fluid source) may thenconnect to the component so as to provide pressure to the controlvolume.

Although not shown in the appended figures, a component may also includea force applicator (e.g., a magnetic drive, a servo, and the like) thatis incorporated into the component. In these embodiments, the user mayconnect the component to an instrument that controllably actuates theforce applicator of the component. In other embodiments, the componentengages with a device that in turn advances the component against thesubject as illustrated in FIG. 1 or, alternatively, pressurizes acontrol volume within the component.

The component may define a control volume of from about 0.01 ml to about100 ml; control volumes in the range of from 1 ml to about 10 ml areconsidered especially suitable.

An osculating surface of the disclosed components may suitably comprisea material having a thickness in the range of from about 0.005 inches toabout 0.060 inches, although these ranges are not exclusive or otherwiselimiting.

A variety of materials may be used in the disclosed components. Anosculating surface may suitably include a material having an ultimateelongation of from about 200% to about 1000%, a 300% modulus of fromabout 1.5 MPa to about 4.0 MPa, an ultimate tensile strength of fromabout 20 MPa to about 40 MPa, or a combination of these.

Components according to the present disclosure may also include aprojection (which may also be termed a “tab”), such as tab 378 in FIG.15A. Such a projection may be adapted to engage with an engagementregion (e.g., a tab-slot engagement) of an instrument or othercomponent. One exemplary embodiment is shown in FIG. 15, which isdescribed in additional detail elsewhere herein.

A component may also include a deflectable projection. The deflectableprojection suitably comprises a material (e.g., a mirrored material)that is reflective to electromagnetic radiation. As described elsewhereherein, deflection of the projection may be monitored so as to determinea pressure exerted on the component.

Components may also include (not shown) a lens. The lens may beconfigured so that it is in optical communication with the osculatingsurface. A lens may also be configured to permit a user to observe oreven illuminate the pupil of the subject or even an intraocular bloodvessel within the subject's eye.

A component may also be constructed such that the component comprises astrain gauge. One such embodiment is shown in FIG. 17, which isdescribed in more detail elsewhere herein. In such an embodiment,deflection caused by applanation/osculation causes an elongation of thematerial of the strain gauge and a related measurable change inelectrical resistance. As shown in the figure, the strain gauge maycomprise a strain gauge pattern disposed on the component, the straingauge pattern being configured to measure deflection of a portion of thecomponent during contact with a subject.

The present disclosure also provides methods of estimating a pressure(e.g., an intraocular pressure, intracranial pressure) in a subject.These methods suitably include imaging an intraocular blood vessel whileapplying a force to the subject's ocular globe, the force being appliedthrough a component having a contact surface that osculates a portion ofthe subject's ocular globe, and the force being sufficient to collapsean intraocular blood vessel.

It should be understood that the term “imaging” does not require aphotographic or videographic image. Imaging should be understood toencompass, e.g., the use of ultrasound to obtain an image of a region(e.g., blood vessel) of interest. Imaging also encompasses MRI, CT, andother techniques that permit visualization of a region of interestwithout also requiring illumination of that region. In one exemplaryembodiment, a user may image an intraocular blood vessel within the eyeby ultrasound while applying a force to a subject's ocular globe whilethe subject's eyelid is closed. In this way, a user may assess thecondition of a subject that is sleeping or even unconscious.

A user may also correlate a force that collapses the intraocular bloodvessel to an estimated intracranial pressure of the subject. Variousmethods for doing so are described elsewhere herein and in U.S. patentapplication Ser. No. 13/309,920, the entirety of which is incorporatedherein by reference.

The force may be applied to, e.g., the cornea of the subject, to thesclera of the subject, to the eyelid of the subject, or a combinationthereof. It should be understood that force may be applied at a discretelocation, across an area, or even at two or more separate locations of asubject's ocular globe.

Force may be applied in a variety of ways. In one embodiment, force maybe applied by physically advancing the component against the subject.This may be accomplished by using a screw drive, a magnetic drive, aservo, or other device to advance the component against the subject. Insome embodiments, at least some of the force may be applied byincreasing a pressure within the component so as to exert a forceagainst the subject, as shown in FIG. 13D and associated description.

A user may measure the deflection of a reflective portion of thecomponent that deflects during force application. This is shown in FIG.16 and associated description. The user may measure radiation reflectedfrom the reflective portion of the component and may also measure achange in radiation related to deflection of the reflective portion ofthe component. The user may (manually or even in an automated fashion)correlate a change in the reflected radiation to the force.

The methods may include application of the force through a contractsurface that is flat, but the surface—as described elsewhere herein—mayalso be characterized as being concave. Suitable concave surfaces aredescribed elsewhere herein; one such suitable surface may have a radiusof curvature greater than about 7 mm, or even greater than about 8 mm.

In some applications of the disclosed methods, the osculated area of theocular globe remains essentially constant during force application. Asshown in FIG. 13B, the osculating surface of osculator 337 is adaptedfor cornea 320 such that the surface area of osculation remainsvirtually constant during a measurement cycle and fills osculator 337immediately upon contact.

The methods may also include the use of a strain gauge of the componentto estimate the force. As described elsewhere herein, a component mayhave a strain gauge disposed on the component, and deflection caused byapplanation/osculation causes an elongation of the material of thestrain gauge and a related measurable change in electrical resistance.

A user may also measure at least of one pupil latency, pupilconstriction velocity, pupil dilation velocity, or any combinationthereof. This may be accomplished by illuminating the retina of thesubject with illumination sufficient to stimulate the retina andinitiate the pupillary reflex, and measuring at least of one pupillatency, pupil constriction velocity, pupil dilation velocity, or anycombination thereof. Pupillary measurements may be performed in anon-contact manner, e.g., the retina may be stimulated without acomponent also contacting the subject's ocular globe. In someembodiments, however, pupillary measurements may be performed while acomponent contacts the ocular globe.

The retinal stimulation may be provided by a fixation light. In someembodiments, the user may use a fixation light on which the subjectfocuses during method operation. The fixation light may be adapted toprovide a stronger illumination when appropriate to stimulate thesubject's retina and to allow the user to monitor the pupil's responseto the stimulation. The user suitably images (e.g., via CCD, ultrasound,or other imager) the pupil's response to the stimulating illumination.The images may be collected and analyzed in real time. Alternatively,the images of the pupil may be recorded and then analyzed at a latertime. A user may also stimulate the retina using an alternative sourceof illumination in addition to (or in place of) a fixation light.

The present disclosure also provides systems for measuring intracranialpressure in a subject. An exemplary system suitably includes anophthalmic component having a having an osculating optical surfaceadapted to contact a subject's globe; and a force applicator.

As explained elsewhere herein, the force applicator may be a device(e.g., a screw drive or other component) that advances the componentagainst the ocular globe of the subject. The force applicator may alsobe a device (e.g., a pump) that pressurizes the control volume of thecomponent so as to exert a force against the subject's ocular globe.

Components suitable for use with the disclosed systems are describedelsewhere herein. A component may feature a flat surface that osculatesthe ocular globe of the subject. A component may also feature anosculating optical surface of the ophthalmic component that ischaracterized as being concave. Such a surface may have a radius ofcurvature of at least about 7 mm.

An ophthalmic component may also be configured to engage an engagementregion of the system. This engagement may be a tab-slot engagement(e.g., FIG. 15). The component may also be press-fitted to theengagement region, screwed to the engagement region, or otherwiseengaged.

The disclosed systems may also include an imager. Suitable imagers(ultrasound devices, MRI, CT, cameras, videocameras, PMTs, and the like)are described elsewhere herein. An imager may be configured to becapable of imaging a subject's pupil, an intraocular blood vessel of thesubject, or another part of a subject's ocular anatomy. Imagers aresuitably configured to collect an image of the cornea, an intraocularblood vessel, the pupil, or any combination thereof. Video images may beanalyzed using Eulearian Video Magnification (“Eulerian VideoMagnification for Revealing Subtle Changes in the World” Frederic(Fredo) Durand, William T. Freeman, John V. Guttag, Michael Rubinstein,Eugene Inghaw Shih and Hao-Yu Wu; Massachusetts Institute of Technologyfor detection of ocular or peri-ocular blood vessel motion detection(e.g. collapse) or pupillary.

As described elsewhere herein, components may include a reflectiveportion. This portion may be a tab or other projection, and is suitablyadapted to deflect when the osculating optical surface of the componentis exerted against a subject's ocular globe. A system may also include adevice configured to illuminate the reflective portion. Systems mayfurther include a device (e.g., linear photo-detector, CCD or PMT) thatis adapted to monitor radiation reflected from the reflective portion,or even adapted to monitor changes in radiation (e.g., change inradiation intensity, change in location of reflected radiation, or both)related to deflection of the reflective portion. A system may be furtherconfigured to correlate a change in radiation reflected from thereflective portion of the component to a force applied through thecomponent.

As described elsewhere herein, a system may also include a source ofillumination. This source of illumination may be, e.g., a fixation lighton which a subject may focus during system operation. The source ofillumination need not be a fixation light, and may even be usedexclusively for retina stimulation. A system's source of illuminationmay be configured to stimulate the retina of the subject. A system mayalso be configured to measure at least one of pupil latency, pupilconstriction velocity, pupil dilation velocity, or any combinationthereof. As described above, this may be accomplished by imaging thepupil's response to pupillary stimulation.

Non-limiting FIG. 13 presents cross sections of various exemplaryosculating caps and osculator surfaces. An osculating cap holds theosculating surface and affixes it to the distal end of an optical moduleor other component. Measuring IOP utilizing osculator caps 335 shown inFIGS. 12 A, B and C is based on osculator force and area as previouslydescribed.

FIG. 13A shows an exemplary osculating cap with an interface describedin FIG. 10D. The distal surface is planar and the proximal surface iscentrally convex surrounded by a planar surface. As osculating cap 335is advanced towards the eye, applanation area 334 (also shown in FIG. 14as 337) increases and is used in combination with applanation force todetermine IOP. The osculation force at an area of applanation equal to adiameter of 3.06 mm is used to calculate resting IOP. The force ofapplanation is directly related to the change in IOP (ΔIOP). Therelationship between applanation force and area with resting IOP is wellestablished (Goldmann). Experiments have demonstrated that forcenecessary to collapse the retinal vessels at applanation areas greaterthan Goldmann measurements (resting IOP measurements), are predictableand repeatable and range from 0-40 g. The degree of osculation capdisplacement following initial corneal contact is typically less thanabout 1 mm to reach about 40 grams force, but may vary based upon thepatients' anatomy and the selected osculating instruments.

Before the present disclosure, there has been little need to explorechanges in IOP with applanation areas substantively greater than 3.06mm. However, a person of ordinary skill in the art can readily determinethe correlation of ΔIOP to resting IOP, force, and applanation area.FIG. 20 shows representative experimental data and trend linesdemonstrating the relationship between applanation force/area to ΔIOPfor several different resting IOPs. The y-axis is force/applanation areaand x-axis is the ΔIOP over resting IOP measured by a pressuretransducer.

FIG. 13B shows alternative device that includes osculating cap 332 andnon-deformable concave osculator 337. The radius of curvature of theosculator 337 is preferably greater than the radius of curvature ofcornea 320. Cornea 320 may essentially fill the concavity ofnon-deformable osculator 337 that contacts the eye. The IOP increaseswhen osculating cap 332 advances with an increasing force. Force can bemeasured using a wide variety of methods including—but not limited to—aforce transducer embedded in the distal side of osculator 337, the backelectro-motive force from a motor advancing the osculator or usingindirect measurements of force as described herein. Osculating surfaceof osculator 337 is essentially matched or otherwise adapted for cornea320 such that the surface area of osculation remains virtually constantduring a measurement cycle and fills osculator 337 immediately uponcontact. As a result of matching the osculating surface to the cornea,pressure of the eye is supported by the entire osculating surface, andreadings for a force transducer embedded on the distal surface aredirectly related to IOP. A tonometer such as the Ziemer Pascal DynamicContour Tonometer (Ziemer USA, Inc. Alton, Ill.) is reasonably suitablefor this purpose. The force can also be measured as described above inFIG. 13A, but because the osculation area is virtually constant duringthe entire measurement period, the osculation area need not be measuredin order to determine ΔIOP.

Using a comparatively large osculating surface area increases theeffective aperture for the retinal imaging and illumination paths overthe applanating cap shown in FIG. 13A. Increasing the aperture canincrease the effective field of view of the retina and increaseillumination performance of the system. Osculator 337 diameter ispreferably larger than or equal to the corneal diameter.

Another method of measuring force for purposes of determining IOP andΔIOP at the osculating cap is shown in exemplary FIG. 13C. In thatfigure, osculating cap 332 comprises semi-rigid deformable osculator338, control volume 345, and proximal port 348 connected to pressuretransducer 350. For retinal imaging purposes semi-rigid osculator 338must be optically clear and can be composed of a thin sheet (e.g., about10 mils to about 60 mils) of flexible material. Optical materials suchas optical aliphatic polyether polyurethane or clear polypropylene-basedsheet are suitable. A suitable range of material properties for thesurface are ultimate elongation of 200-1000%, 300% Modulus of 1.5-4.0MPa, and ultimate tensile strength of 20-40 MPa. The semi-rigiddeformable osculator 338 has a suitable pre-osculating radius ofcurvature greater than the curvature of the cornea (a radius may begreater than about 7 mm or about 8 mm). When the surface osculates thecornea, the osculating surface may slightly deform so as to match thecornea curvature. The eye fills osculator 338 so as to occupy the curvedportion of control volume 345.

Before contact, control volume 345 is at steady-state and the pressureis set at a zero point. Upon contact, control volume 345 compresses, andpressure and force on the eye increase. The osculator 338 and cornea 320deform after the osculator cap contacts the cornea, and the pressure inthe control volume is measured with pressure transducer 350. Dependingon the curvature and material properties of the osculator, when the eyeis osculated the contact area can remain virtually constant or changeduring the measurement period. As the control volume changes due todeformation of the osculator, the pressure measurements will be directlyrelated to the force on the eye and can be calibrated given the materialproperties of the osculating surface and the control volume pressurechange. The IOP is calculated with previously described methods by usingthe force derived from the pressure change and the osculating area. Anexample of a suitable pressure transducer is a solid statepiezoresistive pressure transducer (Omega PX170-07DV) connected to port348 open to the proximal surface of control volume 345. The pressure inthe control volume can be continuously measured and advancement of theosculator will increase the pressure in the control volume and the eye.

FIG. 13D shows osculating cap 332 with an active pneumaticpressurization of deformable elastomeric osculator 339, which conformsto corneal curvature. When control volume 345 is pressurized by pump 349and measured by transducer 350, the control volume pressure is directlyproportional to the pressure in the eye. Control volume 345 can besuitable pressurized with a fluid, e.g., air, water, saline, or otherliquid or gas and delivered to the control volume by a wide variety ofmechanisms including a piston pump 349 actuated manually orelectronically through a pump and computerized controller. The fluid maybe delivered to the control volume via a conduit that places the controlvolume into fluid communication with a fluid reservoir (not shown). Afluid reservoir may be exterior to the osculator cap. As one suchexample, the system may include a squeeze bulb that allows theuser—manually or via automation—to deliver fluid (e.g., air) to thecontrol volume from the environment exterior to the cap. A suitableelastomeric osculator for retinal imaging purposes may be opticallyclear. A suitable cap may also comprise a thin film (e.g., 0.5-25 mils)of flexible material. Optical materials such as optical aliphaticpolyether polyurethane or clear polypropylene-based films are suitable.A suitable range of material properties for the surface are ultimateelongation of 200-1000%, a 300% Modulus of 1.5-4.0 MPa, and an ultimatetensile strength of 20-40 MPa. The elastomeric osculator is suitablyless rigid than the cornea of the eye so that the elastic surface atleast partially osculates the eye when contacted to the cornea.

To determine the retinal vessel pressure, osculating cap 349 in FIG. 13Dis first supported on the cornea such that osculator 339 conforms to thecornea, and does not exert a significant pressure over atmosphericpressure. This can be achieved by allowing the control volume pressureto equalize to atmospheric by venting to the atmosphere or reduction ofpressure by suction. After the cornea is supported by the thin filmosculator, the pressure in the control volume is increased until theretinal vessel collapses. Because the osculating interface 334 is incontact and supported by the cornea, the pressure in control volume 345is proportionally equal to the IOP. For osculating cap 332 in FIG. 13D,resting IOP need not be determined for determination of ICP. Usingosculating cap 332 also obviates the need to advance osculator cap 332to increase IOP. It should be understood that a user may advance anosculator cap that comprises a pressurizable control volume and may evenpressurize the control volume while advancing the cap, although this maynot be necessary.

FIG. 14 shows representative images taken with the methods and apparatusdescribed herein and shown in FIGS. 5, 6, 7, 8, 9, 10D, 13A andosculating cap 380 shown in FIGS. 15 and 17. FIG. 14 shows human retinalimages of the optic disc (L) and cornea images of the osculationinterface 334 (R). The top row of FIG. 14 shows retina 330 upon initialosculation and prior to CRV collapse. The arrows in FIG. 14 (L) show thelocation of CRV prior to (top) and post (lower) CRV collapse. The rightimages are representative of the cornea osculation area 337 prior to(upper) and post (lower) CRV collapse.

FIGS. 15 and 16 illustrate alternative, non-limiting methods ofdetermining the contact force between the ocular globe and an instrument(e.g., an osculating cap) by measuring deflection of a portion of theosculating cap in response to osculation of the cornea.

In FIG. 15 osculating cap 380 via cap extension 378 engage with and areremovably affixed to cap holder 390 permanently attached to the distalend of the optical train (not shown). FIG. 15A illustrates osculatingcap 380 prior top engagement with cap holder 39 and FIG. 15B illustratedosculating cap 380 after engagement. Hinge 379 located on cap extension378 allows rotation of the osculation cap 380 such that reflecting tab392 presses onto rod 393 and causes a deflection in the position of thereflecting tab 392. Reflecting tab 392 is configured such thatelectromagnetic energy from light source and lens 395 is reflected orscattered from the proximal side of reflecting tab 392. Selection of thereflectivity, index of refraction or even surface finish arerepresentative examples of the many ways to suitable reflect or scatterlight from reflecting tab 392. Osculating cap 380 may be configured sothat a small amount of rotation, preferably less than 1 degree, occursin response to varying degrees of osculation force. This small rotationis configured to induce a deflection (which may be comparatively large)of reflecting tab 392 away from the cap holder 390. The magnitude of thedeflection is dependent on the osculation force. One exemplary materialfor cap 380 and reflecting tab 392 is poly methyl methacrylate (PMMA). Aforce of 1 to 40 grams pressing on the cap can cause a range ofdeflections from 1 to 40 microns, depending on the thickness and widthof the tab.

As shown in FIG. 16A and FIG. 16B, force F from the cornea directedagainst osculator cap 380 may result in the rotation of osculator cap380, which in turn results in the deflection of reflecting tab 392 orother structure of the osculator cap as it is held in place. A dottedline (labeled with “Zero deflection”) represents the position for thereflection tab 392, when zero force applied. Light source and lens 395provides electromagnetic radiation (e.g., visible or infrared light froman LED, laser or other illumination source, ultrasound, and the like)directed onto and reflected from reflection tab 392 and collected byphotodetector 396 or similarly appropriate electromagnetic sensor. Thelight source and lens 395 and photodetector 396—e.g., shown in FIG. 16Aand FIG. 16B—may be configured such that contact with the cornea canresult in changes in the light position, intensity or the like. Suitableelectromagnetic energy by be reflected or scattered to induce ameasureable change detectable by photosensor 396. By way of exampleonly, a suitable photodetector is a TSL1401CL linear sensor array(AMS-TOAS, Inc. Plano, Tex.) used in conjunction with an LED emitting400 nm to 1000 nm of light. When osculator cap 380 contacts the eye,reflection tab 392 is deflected and the position of light is sensed byphotodetector 392. By selection of the physical characteristics ofreflecting tab 392, the signal from photodetector 392 may be calibratedto indicate the force of osculation. Other means of measuring deflectioncan be used and may include contact devices such as a linear variabledifferential transformer (LVTD) or distributed impedance sensortechnology (DIST) and non-contact devices such as a differentialvariable reluctance transducer (DVRT).

FIG. 16C shows an exemplary configuration of components to performoptical comparative flat interferometry using monochromatic collimatedlight and lens 395 and beam splitter 398 to image the interferencefringe patterns generated by the reflection of light off of referenceflat 399 and the deflected surface 392. Reference surface 399 can beplaced either in line or orthogonal to the deflecting surface dependingon geometrical constraints. By counting the number of interference bands(also called fringes) and deviation from zero deflection, one candetermine a change in parallelism related to light source wavelength.The number of fringes corresponds to the degree of deflection (tilt)between the reference flat and the deflecting surface with a singlefringe corresponding to the distance equal to the wavelength of thelight source.

FIG. 17 shows a strain gauge pattern on an osculator to measure theforce exerted on the cornea. A thin strain sensitive material 342 can bemounted on the proximal side of the osculator cap surface and used as astrain gauge to measure the deflection of the cap surface. In theexample shown, a suitable material such as Mylar™ is bonded to thesurface in a pattern such that a small deflection caused byapplanation/osculation will cause an elongation of the material and ameasurable change in electrical resistance.

FIG. 18 illustrates a method to removably hold in place osculating cap380. The osculating cap 380 has locking tabs 381 that are aligned to fitand engage a spring-loaded mechanism 382 actuating pin 383 which piercestab 381, locking it in place. In this configuration, as osculation cap380 is rotated clockwise and the tabs 381 pushes a cam 384 thatcompresses a spring-loaded pin so that the tab can engage the pin.

Optical elements in the present invention may be configured such thatthere may be imaging of optical structures from the cornea through theretina. As a result, images of the iris may also be collected andanalyzed. This function is of value to the medical professionaldiagnosing brain injury. Pupillary reflex assessment is a fundamentalpart of the neurological examination. Changes in size and reactivity ofthe pupil to bright light stimuli can be a sign of neurologicaldeterioration. In particular, the pupillary reflex can be analyzed toquantify clinically relevant variables including: (1) Latency—the timefrom the beginning of the light stimulus and the beginning of pupilconstriction, (2)—Constriction velocity—the velocity of pupilconstriction measured as change in pupil area divided by time, and(3)—Dilation velocity—the velocity of pupil dilation measured as changein pupil area divided by time.

FIG. 19 presents a representative image of the human eye 305 from theICP system with computer image analysis highlighting the pupil area 311.The right image shows two data streams collected by the ICP system toperform pupillometry and the relevant parameters for the medicalprofessional. The lower stream shows the period of illumination from abright light stimuli 310. The upper data stream shows the response ofthe pupil to bright light stimuli 310. In this plot, the y-axis showsthe area of the pupil 311 against the x-axis showing time in seconds.The two plots are synchronized in time.

The disclosed systems, by using images, sensors, and processors (whichmay be independent of ICP measurement or be integrated into the ICPmeasurement process), data from the pupil can be easily obtained. Thisinvention can illuminate the eye and initiate the pupillary reflex andrecorded images (e.g., video) may be analyzed to quantify pupil latency,constriction velocity, and dilation velocity. Pupillometry can beperformed during measurement of ICP. Further, it can be performedindependent of ICP measurements.

Osculation of the ocular globe is not necessary for performingpupillometry. For example, osculation cap in FIG. 13B would not requireosculation to image the pupil and perform pupillometry. The measurementof pupillary reflex is suitably performed on both left and right eyes asit can provide valuable information not only about brain injury but alsoabout optic nerve or oculomotor nerve damage.

The disclosed technology has been shown and described with reference toexemplary drawings and not drawn to scale. It will be understood by oneof skill in the art that various changes in detail may be effectedwithout departing from the scope or spirit of the invention as definedby the claims.

What is claimed:
 1. An ophthalmic component, comprising: a body havingan osculating surface adapted to osculate a subject's ocular globe, andthe body being adapted to engage with an instrument.
 2. The ophthalmiccomponent of claim 1, wherein the osculating surface is characterized asbeing a concave optical surface having a radius of curvature.
 3. Theophthalmic component of claim 2, wherein the radius of curvature of theconcave optical surface is greater than the radius of curvature of asubject's cornea.
 4. The ophthalmic component of claim 2, wherein theradius of curvature of the concave optical surface is greater than about7 mm.
 5. The ophthalmic component of claim 1, wherein the osculatingsurface comprises a deformable material.
 6. The ophthalmic component ofclaim 1, wherein the component defines an enclosed control volume inmechanical communication with the osculating surface.
 7. The ophthalmiccomponent of claim 6, wherein the control volume is configured to bepressurized while in contact with a subject's ocular globe.
 8. Theophthalmic component of claim 6, further comprising a passage placingthe control volume into fluid communication with the environmentexterior to the control volume.
 9. The ophthalmic component of claim 1,wherein the osculating surface comprises a material having a thicknessin the range of from about 0.005 inches to about 0.060 inches.
 10. Theophthalmic component of claim 1, wherein the osculating surfacecomprises a material having an ultimate elongation of from about 200% toabout 1000%, a 300% modulus of from about 1.5 MPa to about 4.0 MPa, aultimate tensile strength of from about 20 MPa to about 40 MPa, or anycombination thereof.
 11. The ophthalmic component of claim 1, furthercomprising a projection adapted to engage with an instrument.
 12. Theophthalmic component of claim 1, further comprising a deflectableprojection.
 13. The ophthalmic component of claim 12, wherein thedeflectable projection comprises a material that is reflective toelectromagnetic radiation.
 14. The ophthalmic component of claim 1,further comprising a lens in optical communication with the osculatingsurface.
 15. The ophthalmic component of claim 1, further comprising astrain gauge.
 16. The ophthalmic component of claim 15, wherein thestrain gauge comprises a strain gauge pattern disposed on the component,the strain gauge pattern being configured to measure deflection of aportion of the component during contact with a subject.
 17. A method ofestimating a pressure in a subject, comprising: imaging an intraocularblood vessel while applying a force to the subject's ocular globe, theforce being applied through a component having a contact surface thatosculates a portion of the subject's ocular globe, the force beingsufficient to collapse an intraocular blood vessel.
 18. The method ofclaim 17, further comprising correlating the force that collapses theintraocular blood vessel to an estimated intracranial pressure of thesubject.
 19. The method of claim 17, wherein the force is applied to thecornea of the subject, to the sclera of the subject, to the eyelid ofthe subject, or any combination thereof.
 20. The method of claim 17,wherein at least some of the force is applied by advancing thecomponent.
 21. The method of claim 17, wherein at least some of theforce is applied by increasing a pressure within the component so as toexert a force against the subject.
 22. The method of claim 17, furthercomprising measuring the deflection of a reflective portion of thecomponent that deflects during force application.
 23. The method ofclaim 22, further comprising measuring radiation reflected from thereflective portion of the component.
 24. The method of claim 22, furthercomprising measuring a change in radiation related to deflection of thereflective portion of the component.
 25. The method of claim 17, whereinthe contact surface is characterized as being concave.
 26. The method ofclaim 25, wherein the contact surface has a radius of curvature greaterthan about 7 mm.
 27. The method of claim 17, wherein the osculated areaof the ocular globe remains essentially constant during forceapplication.
 28. The method of claim 17, further comprising using astrain gauge of the component to estimate the force.
 29. The method ofclaim 17, further comprising illuminating the pupil of the subject withillumination sufficient to stimulate the pupil
 30. The method of claim29, further comprising measuring at least of one pupil latency, pupilconstriction velocity, pupil dilation velocity, or any combinationthereof.
 31. A system for measuring intracranial pressure in a subject,comprising: an ophthalmic component having a having an osculatingoptical surface adapted to contact a subject's ocular globe; and a forceapplicator.
 32. The system of claim 31, wherein the osculating opticalsurface of the ophthalmic component is characterized as being concaveand has a radius of curvature of at least about 7 mm.
 33. The system ofclaim 31, wherein the ophthalmic component is configured to engage anengagement region of the system.
 34. The system of claim 31, wherein theforce applicator is configured to advance the ophthalmic componentagainst a subject's ocular globe.
 35. The system of claim 31, whereinthe force applicator is configured to increase a pressure within theophthalmic component.
 36. The system of claim 31, further comprising animager.
 37. The system of claim 31, wherein the imager is configured tocollect an image of the cornea, an intraocular blood vessel, the pupil,or any combination thereof.
 35. The system of claim 31, wherein thecomponent comprises a reflective portion adapted to deflect when theosculating optical surface of the component is exerted against asubject's ocular globe.
 36. The system of claim 35, further comprising adevice configured to illuminate the reflective portion.
 37. The systemof claim 35, wherein the system is configured to measure radiationreflected from the reflective portion of the component, to measure achange in radiation reflected from the reflective portion of thecomponent, or both.
 38. The system of claim 35, the system beingconfigured to correlate a change in radiation reflected from thereflective portion of the component to a force applied through thecomponent.
 39. The system of claim 35, further comprising a source ofillumination.
 40. The system of claim 39, wherein the source ofillumination is configured to stimulate the pupil of the subject. 41.The system of claim 40, wherein the system is configured to measure atleast of one pupil latency, pupil constriction velocity, pupil dilationvelocity, or any combination thereof